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A structural variation reference for medical and population genetics

Collins, Ryan L ; Brand, Harrison ; Karczewski, Konrad J ; Zhao, Xuefang ; Alföldi, Jessica ; Francioli, Laurent C ; Khera, Amit V ; Lowther, Chelsea ; Gauthier, Laura D ; Wang, Harold ; Watts, Nicholas A ; Solomonson, Matthew ; O'Donnell-Luria, Anne ; Baumann, Alexander ; Munshi, Ruchi ; Walker, Mark ; Whelan, Christopher W ; Huang, Yongqing ; Brookings, Ted ; Sharpe, Ted ; Stone, Matthew R ; Valkanas, Elise ; Fu, Jack ; Tiao, Grace ; Laricchia, Kristen M ; Ruano-Rubio, Valentin ; Stevens, Christine ; Gupta, Namrata ; Cusick, Caroline ; Margolin, Lauren ; Taylor, Kent D ; Lin, Henry J ; Rich, Stephen S ; Post, Wendy S ; Chen, Yii-Der Ida ; Rotter, Jerome I ; Nusbaum, Chad ; Philippakis, Anthony ; Lander, Eric ; Gabriel, Stacey ; Neale, Benjamin M ; Kathiresan, Sekar ; Daly, Mark J ; Banks, Eric ; MacArthur, Daniel G ; Talkowski, Michael E

Nature (London), 2020-05, Vol.581 (7809), p.444-451 [Peer Reviewed Journal]

England: Nature Publishing Group

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Title:
A structural variation reference for medical and population genetics
Author: Collins, Ryan L ; Brand, Harrison ; Karczewski, Konrad J ; Zhao, Xuefang ; Alföldi, Jessica ; Francioli, Laurent C ; Khera, Amit V ; Lowther, Chelsea ; Gauthier, Laura D ; Wang, Harold ; Watts, Nicholas A ; Solomonson, Matthew ; O'Donnell-Luria, Anne ; Baumann, Alexander ; Munshi, Ruchi ; Walker, Mark ; Whelan, Christopher W ; Huang, Yongqing ; Brookings, Ted ; Sharpe, Ted ; Stone, Matthew R ; Valkanas, Elise ; Fu, Jack ; Tiao, Grace ; Laricchia, Kristen M ; Ruano-Rubio, Valentin ; Stevens, Christine ; Gupta, Namrata ; Cusick, Caroline ; Margolin, Lauren ; Taylor, Kent D ; Lin, Henry J ; Rich, Stephen S ; Post, Wendy S ; Chen, Yii-Der Ida ; Rotter, Jerome I ; Nusbaum, Chad ; Philippakis, Anthony ; Lander, Eric ; Gabriel, Stacey ; Neale, Benjamin M ; Kathiresan, Sekar ; Daly, Mark J ; Banks, Eric ; MacArthur, Daniel G ; Talkowski, Michael E
Subjects: Amino acid sequence ; Analysis ; Autism ; Basic Medicine ; Biologi ; Biological Sciences ; Deoxyribonucleic acid ; Diagnostic systems ; Disease ; Disease - genetics ; DNA ; Female ; Gene mapping ; Gene sequencing ; Genetic screening ; Genetic Testing ; Genetic Variation ; Genetics ; Genetics, Medical - standards ; Genetics, Population - standards ; Genetik ; Genome, Human - genetics ; Genomes ; Genomic libraries ; Genomic structural variations ; Genomics ; Genotyping Techniques ; Human population genetics ; Humans ; Life Sciences ; Male ; Medical and Health Sciences ; Medical Genetics ; Medicin och hälsovetenskap ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; Middle Aged ; Mutation ; Natural Sciences ; Natural selection ; Naturvetenskap ; Nucleotides ; Pipelines ; Polymorphism, Single Nucleotide - genetics ; Population genetics ; Population studies ; Properties ; Proteins ; Quality ; Racial Groups - genetics ; Reference Standards ; Regulatory sequences ; Selection, Genetic ; Whole Genome Sequencing
Is Part Of: Nature (London), 2020-05, Vol.581 (7809), p.444-451
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: Structural variants (SVs) rearrange large segments of DNA and can have profound consequences in evolution and human disease . As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral in the interpretation of single-nucleotide variants (SNVs) . However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage . We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings . This SV resource is freely distributed via the gnomAD browser and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
Publisher: England: Nature Publishing Group
Language: English

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A structural variation reference for medical and population genetics

England: Nature Publishing Group

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